Panini invented a way of seeing Rome that tourists still use. His paintings of the Pantheon interior, the Forum and the Colosseum established the visual conventions for depicting ancient ruins that persisted through two centuries of Grand Tour painting and into modern photography. He was so precise in his architectural reconstructions that he carefully edited out later additions, removing Bernini's bell towers from the Pantheon's pediment and stripping walled-in arches from the Theatre of Marcellus.

He was born in Piacenza in 1691 and trained under Giuseppe Natali, the stage designer Francesco Galli-Bibiena, and Andrea Galluzzi. He settled in Rome in 1711 and entered the studio of Benedetto Luti. His early career was in palace decoration: the Villa Patrizi (1719), the Palazzo de Carolis (1720) and the Seminario Romano (1721). But veduta painting, views of real and imagined Rome, became his principal occupation.

His vedute split into two modes. Some were topographically faithful; others were capricci, fanciful rearrangements of monuments that compressed centuries of Roman architecture into a single composition. Both types were bought by European collectors, royalty and Grand Tourists who wanted a portable version of the city to take home. The Spanish monarchs were particularly avid patrons; several Panini paintings remain in the Prado.

He taught perspective and optics at the French Academy in Rome, where his students included Hubert Robert and the stage designer Giovanni Niccolo Servandoni. His methods were later formalised into the "Panini projection", a mathematical technique for rendering panoramic views. He was elected director of the Accademia di San Luca in 1754. He died in Rome in 1765.